Tobias Raabe presented a pioneering approach to modelling and treating metabolic dysfunction-associated steatohepatitis (MASH), a chronic liver disease that affects millions and currently lacks effective drug therapies. Raabe began by highlighting the challenges posed by MASH, noting that liver transplantation remains the only definitive cure, and decades of research using animal models have produced limited breakthroughs. Recent advances in single-cell analysis have revealed new cellular pathways, such as the activation of TREM2 macrophages, which are specific to MASH-affected livers.
Raabe’s team developed organoids from MASH patient livers, discovering that these organoids expand more slowly and display larger cell sizes than those derived from healthy livers. These organoids also exhibit marked overexpression of genes associated with cellular senescence, closely mirroring disease features such as hepatocyte ballooning. To create a more representative human fibrosis model, the team combined these organoids with macrophages and myofibroblasts sourced from healthy donors. This innovative system successfully achieved fibrotic scar formation in vitro and is compatible with high-throughput screening, enabling the testing of all possible cell-type combinations. The resulting cellular architecture and interactions closely resemble those observed in human MASH livers.
A major advancement in Raabe’s ongoing work is the use of lipid nanoparticles (LNPs) for cell-type specific gene targeting within the 3D MASH model. Collaborating with leading research laboratories, the team has developed LNPs that selectively target hepatocytes, macrophages, and myofibroblasts. Notably, they have achieved efficient knockdown of the YAP protein in myofibroblasts, inducing senescence without affecting parenchymal cells – a promising therapeutic strategy. Furthermore, the team has identified a novel cell death pathway in myofibroblasts using both siRNA and chemical compounds delivered via LNPs, with minimal off-target effects on hepatocytes.
Raabe emphasised that future therapies should move beyond single-target drugs, advocating for simultaneous targeting of multiple cell types using LNPs. This approach, which is currently under active collaboration, holds promise for more effective treatment of MASH by inhibiting fibrosis while promoting hepatocyte regeneration.
